Implementing computational methods in tandem with synonymous gene recoding for therapeutic development

Synonymous gene recoding, the substitution of synonymous variants into the genetic sequence, has been used to overcome many production limitations in therapeutic development. However, the safety and efficacy of recoded therapeu-tics can be difficult to evaluate because synonymous codon substitutions can re-sult in subtle, yet impactful changes in protein features and require sensitive methods for detection. Given that computational approaches have made signifi-cant leaps in recent years, we propose that machine-learning (ML) tools may be leveraged to assess gene-recoded therapeutics and foresee an opportunity to adapt codon contexts to enhance some powerful existing tools. Here, we examine how synonymous gene recoding has been used to address challenges in thera-peutic development, explain the biological mechanisms underlying its effects, and explore the application of computational platforms to improve the surveillance of functional variants in therapeutic design.